Faecal incontinence affects around 2% of the adult population1. It is even more prevalent in the elderly, and it is likely that many people do not seek help for their symptoms. The most common cause of faecal incontinence is damage to the anal sphincter complex during childbirth2, either through pudendal neuropathy or direct trauma as a result of childbirth. Faecal incontinence may also be seen in the absence of structural injury; in such circumstances, isolated degeneration of the internal anal sphincter (IAS) is the most common cause3.
Conservative measures for mild symptoms of incontinence includes pads4, plugs5, anti-diarrheal medications6 and dietary modification. Some cases will not be controlled with such measures, however. Damage to the external anal sphincter may be amenable to overlapping surgical repair7 though results of internal sphincter repair have been disappointing8. More extensive surgical procedures do exist for more profound damage, including the artificial bowel sphincter9, sacral nerve stimulation10 and graciloplasty11. These are major interventions and may be either unsuitable or poorly tolerated by many patients.
The use of topical agents for the treatment of faecal incontinence is a different approach to an old problem. WO98/27971 proposes the use of a variety of agents in the treatment of faecal incontinence. Those agents include α-adrenoceptor agonists, nitric oxide synthase inhibitors, prostaglandin F2α, dopamine, morphine, β-blockers, and 5-hydroxytryptamine. However, experimental data is given only for phenylephrine, and the nitric oxide synthase inhibitor Nω-nitro-L-arginine.
All clinical research on topical therapies for faecal incontinence has, to date, been focused on phenylephrine, an α-1 adrenoceptor agonist. (Such agents were previously called α-1 adrenergic agonists.) The use of topical phenylephrine is alleged to produce a dose-dependent rise in resting anal canal pressure of normal human subjects. When applied to the anus of normal human subjects, a gel comprising 10% by weight phenylephrine produced a 33% rise in resting anal pressure that was sustained for a median of 7 hours12, see also WO98/27971. The use of topical phenylephrine gels was repeated in patients with ultrasonographically normal anal sphincters, but low resting anal canal pressures and symptoms of incontinence. In this group, however, no significant rise in resting anal pressure was seen with 10% to 20% by weight phenylephrine gels, although increases did achieve statistical significance in those subjects treated with 30% and 40% gels13. This data suggests that the internal anal sphincter of patients with incontinence is less sensitive to adrenoceptor agonists than the sphincter in normal subjects. There is data to support this from in vitro studies, too14.
This fact may also explain why, when the work using phenylephrine was extended to a randomized controlled trial including 36 patients with incontinence and ultrasonographically normal sphincters, no significant overall improvements were seen in incontinence scores, resting anal canal pressure or anodermal blood flow when using 10% phenylephrine gels15. By contrast, in a small, randomized controlled trial of patients with faecal leakage after ileoanal pouch construction, 10% phenylephrine gel was found to produce a significantly greater subjective improvement in continence compared to placebo16.
These results show that, to be effective for treatment of faecal incontinence, it will be necessary for topical phenylephrine preparations to contain high concentrations of phenylephrine, of the order of 30-40% by weight. At these levels, perianal burning has been reported15. For that reason alone, such preparations are not suitable for use in treatment.
Phenylephrine, which acts on α-adrenergic receptors of the vascular musculature, has hypertensive effects, also known as anti-hypotensive or pressor effects, and has been used systemically in the treatment of hypotensive states. Another concern with the topical use of phenylephrine for treatment of faecal incontinence is that, at the high doses required to treat faecal incontinence effectively, i.e. using topical preparations containing 30 to 40% by weight of phenylephrine, the topically administered α-adrenoceptor agonist could act systemically on the vasculature, affecting blood pressure and/or pulse rate.
These concerns regarding the topical use of high doses of an α-adrenoceptor agonist in the treatment of faecal incontinence are supported by the facts that cardiovascular side effects are seen when phenylephrine is applied topically in ophthalmology17, and that local irritation is also observed18. These concerns also apply to other α-adrenoceptor agonists that act on the α-adrenergic receptors of the vasculature, which agonists have similar vasoconstrictor and hypertensive properties as phenylephrine, and which may be used for the same indications as phenylephrine i.e. as a pressor agent and as a vasoconstrictor agent. Methoxamine (2-amino-1-(2,5-dimethoxyphenyl)-1-propanol) is an example of such an α-adrenoceptor agonist.
Methoxamine has two chiral centres and hence has four stereoisomers. The methoxamine currently used clinically as a pressor agent and as a vasoconstrictor agent, is in the form of a mixture of isomers.
Fujita and Hiyama19 have described what is said to be a method for the erythro-directed reduction of α-substituted alkanones by means of hydrosilanes in acidic media. One of the compounds produced is said to be (1R,2S)-2-amino-1-(2,5-dimethoxyphenyl)-1-propanol, which is also called L-erythro-methoxamine by Fujita and Hiyama. However, Fujita and Hiyama did not identify the putative 1R,2S-methoxamine isomer (or any other isomer they produced) definitively i.e. by single crystal X-ray diffractometry, nor did they make any investigations as to the biological activity of the putative 1R,2S-methoxamine isomer (or any other isomer they produced). Furthermore, although the synthetic method described is suitable for producing small amounts, of about 1 g, of the product, we found that the method did not yield the alleged 1R,2S-isomer selectively when scaled up to produce amounts larger than about 1 g, for example, for example, to produce about 30 g to 50 g of the isomer.
The method of Fujita and Hiyama involves the reduction of an α-aminoketone to an alcohol. The authors point out that over-reduction to the hydrocarbon was commonly observed in previously described methods for reducing an α-aminoketone. The authors state that, using their method, formation of the hydrocarbon was not detected by common analytical methods. They state that, in addition, highly erythro selective reduction was recognized. Selectivity of >99% said to be observed.
Although we obtained similar results when producing the alleged 1R,2S-isomer of methoxamine (L-erythro-methoxaine) on a small scale, of about 1 g, on scaling up to 30 g to 50 g batches we found that, contrary to the findings of Fujita and Hiyama, over-reduction did occur, with more than 60% to 70% of the product being the hydrocarbon instead of the desired alcohol. Furthermore, the process was not erythro selective. Substantial amounts of the threo isomer were formed.
Fujita and Huiyama use both the “R,S” nomenclature and the “erythro/threo” nomenclature when referring to their method and the isomers produced. As the Cahn-Ingold-Prelong “R,S” nomenclature is generally accepted as defining an isomer unambiguously, the “R,S” terminology rather than the “erythro/threo” terminology is used herein to define methoxamine isomers.